The compounds of the present invention are new.
Anti-cancer therapeutic requirements call for the constant development of new anti-tumour agents with the aim of obtaining medicaments that are simultaneously more active and better tolerated.
In addition to the fact that the compounds of the invention are new, they exhibit anti-tumour properties that are of special interest.
The present invention relates more specifically to the compounds of formula (I): 
wherein:
R represents:
a hydrogen atom,
a linear or branched (C1-C6)alkyl group optionally substituted by a carboxy group, by a linear or branched (C1-C6)alkoxycarbonyl group or by a NR10R11 group (wherein R10 and R11, which may be identical or different, each represents a linear or branched (C1-C6)alkyl group or together, with the nitrogen carrying them, form a nitrogen-containing heterocycle),
or a linear or branched (C1-C6)alkenyl group,
R1 to R8, which may be identical or different, each represents:
a hydrogen atom,
a linear or branched (C1-C6)alkyl group optionally substituted by an aryl, carboxy or linear or branched (C1-C6)alkoxycarbonyl group,
a hydroxy group,
a linear or branched (C1-C6)acyloxy group,
a group of formula NR12R13, wherein R12 and R13, which may be identical or different, each represents a hydrogen atom or a linear or branched (C1-C6)alkyl group optionally substituted by a group of formula NR14R15, wherein R14 and R15, which may be identical or different, each represents a linear or branched (C1-C6)-alkyl group or together, with the nitrogen atom carrying them, form a nitrogen-containing heterocycle,
a carboxy group,
a linear or branched (C1-C6)alkoxy group optionally substituted by an aryl group or by a group of formula NR14R15, wherein R14 and R15, which may be identical or different, each represents a linear or branched (C1-C6)alkyl group or together, with the nitrogen atom carrying them, form a nitrogen-containing heterocycle,
a linear or branched (C1-C6)alkenyloxy group,
or one of the groups R1 to R8 forms, with another of the groups R1 to R8 that is adjacent, a (C1-C2)alkylenedioxy group,
X represents an oxygen atom or an NR16 group, wherein R16 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group, an aryl group or an aryl-(C1-C6)alkyl group in which the alkyl moiety may be linear or branched,
R9 represents a hydrogen atom or an aryl, heteroaryl, or linear or branched (C1-C6)alkyl group, wherein the alkyl group optionally contains one or more unsaturations and is optionally substituted by one or more identical or different groups selected from aryl, heteroaryl, (C3-C8)cycloalkyl, cyano and NR17R18 (wherein R17 and R18, which may be identical or different, each represents a linear or branched (C1-C6)alkyl group or together, with the nitrogen atom carrying them, form a nitrogen-containing heterocycle),
to isomers thereof, and also to addition salts thereof with a pharmaceutically acceptable acid or base.
Isomers are to be understood as optical isomers and geometrical isomers of the C=N X R9 double bond.
Among the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, benzenesulphonic acid, camphoric acid, etc.
Among the pharmaceutically acceptable bases there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
An aryl group is to be understood as phenyl, biphenylyl or naphthyl, each of those groups optionally being substituted by one or more identical or different groups selected from halogen, linear or branched (C1-C6)alkyl (optionally substituted by one or more halogen atoms), linear or branched (C1-C6)alkenyl (optionally substituted by a phenyl group), linear or branched (C1-C6)alkoxy (optionally substituted by a phenyl group), phenoxy, nitro, cyano, amino (optionally substituted by one or two linear or branched (C1-C6)alkyl groups) and (C1-C2)alkylenedioxy.
A heteroaryl group is to be understood as an aromatic mono- or bi-cyclic group having from 5 to 12 ring members containing one, two or three hetero atoms selected from oxygen, nitrogen and sulphur, wherein the heteroaryl may optionally be substituted by one or more identical or different groups selected from halogen, linear or branched (C1-C6)-alkyl, hydroxy, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)polyhaloalkyl, and amino (optionally substituted by one or more linear or branched (C1-C6)alkyl groups). Amongst the heteroaryl groups the following groups may be mentioned without implying any limitation: thienyl, pyridyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, isoquinolyl, pyrimidinyl, thiadiazolyl.
Preferred heteroaryl groups are thienyl, pyridyl, furyl and thiadiazolyl groups.
A nitrogen-containing heterocycle is to be understood as a saturated monocyclic group having from 5 to 7 ring members containing one, two or three hetero atoms, one of those hetero atoms being a nitrogen atom, and the additional hetero atom or atoms optionally present being selected from the atoms oxygen, nitrogen and sulphur. Preferred nitrogen-containing heterocycles are the groups pyrrolidinyl, piperidyl, morpholinyl and piperazinyl.
Preferred compounds of formula (I) are those wherein X represents an oxygen atom.
Preferred compounds of formula (I) are those wherein R1 to R6 and R8, which may be identical or different, each represents a hydrogen atom, a hydroxy group or a linear or branched (C1-C6)alkoxy group.
Preferred compounds of formula (I) are those wherein R7 represents a 2-dimethylaminoethoxy group or a 2-(1-pyrrolidinyl)-ethoxy group.
Amongst the preferred compounds of formula (I), the following, more especially, may be mentioned:
(10Z)-8-(2-dimethylaminoethoxy)-2,3-dimethoxyindeno[1,2-b]indole-10(5H)-one O-(1-phenyl-2-propynyl)oxime, isomers thereof, and addition salts thereof with a pharmaceutically acceptable acid,
(10Z)-8-(2-dimethylaminoethoxy)-2,3-dimethoxyindeno[1,2-b]indole-10(5H)-one O-(2-propynyl)oxime, isomers thereof, and addition salts thereof with a pharmaceutically acceptable acid,
(10Z)-8-(2-dimethylaminoethoxy)-2,3-dimethoxyindeno[1,2-b]indole-10(5H)-one O-(1-methyl-2-propynyl)oxime, isomers thereof, and addition salts thereof with a pharmaceutically acceptable acid,
(10Z)-8-(2-dimethylaminoethoxy)-2,3-dimethoxyindeno[1,2-b]indole-10(5H)-one O-[1-(3-furyl)-2-propynyl]oxime, isomers thereof, and addition salts thereof with a pharmaceutically acceptable acid,
(10Z)-8-(2-(1-pyrrolidinyl)ethoxy)-2,3-dimethoxyindeno[1,2-b]indole-10(5H)-one O-[1-(3-furyl)-2-propynyl]oxime, isomers thereof, and addition salts thereof with a pharmaceutically acceptable acid,
and (10Z)-8-(2-dimethylaminoethoxy)-2,3-dimethoxyindeno[1,2-b]indole-10(5H)-one O-((1S)-1-methyl-2-propynyl)oxime, isomers thereof, and addition salts thereof with a pharmaceutically acceptable acid.
The invention extends also to a process for the preparation of compounds of formula (I) which is characterised in that a compound of formula (II): a
wherein R1, R2, R3 and R4 are as defined for formula (I), is reacted
with N-bromosuccinimide to yield a compound of formula (III): 
wherein R1, R2, R3 and R4 are as defined hereinbefore,
which is reacted with triphenylphosphine to yield a compound of formula (IV): 
wherein R1, R2, R3 and R4 are as defined hereinbefore,
which is reacted with a compound of formula (V): 
wherein R1, R6, R7 and R8 are as defined for formula (I),
to yield a compound of formula (VI): 
wherein R1, R2, R3, R4, R5, R6, R7 and R8 are as defined hereinbefore,
which is placed in the presence of a base to yield a compound of formula (VII): 
wherein R1, R2, R3, R4, R5, R6, R7 and R8 are as defined hereinbefore,
which is subjected to the action of a reducing agent to yield, after separation of isomers where necessary, a compound of formula (VIII): 
wherein R1, R2, R3, R4, R5, R6, R7 and R8 are as defined hereinbefore,
which is reacted, if desired, with a compound of formula (IX):
Rxe2x80x2xe2x80x94Zxe2x80x83xe2x80x83(IX)
wherein Rxe2x80x2 represents a linear or branched (C1-C6)alkyl group (optionally substituted by an aryl group or by an NR9R10 group, wherein R9 and R10, which may be identical or different, each represents a linear or branched (C1-C6)alkyl group or together, with the nitrogen atom carrying them, form a nitrogen-containing heterocycle) or a linear or branched (C1-C6)alkenyl group, and Z represents a leaving group, such as, for example, a halogen atom or a mesylate, tosylate or trifluoromethanesulphonate group,
to yield a compound of formula (X): 
wherein R1, R2, R3, R4, R5, R6, R7, R8 and Rxe2x80x2 are as defined hereinbefore,
which compounds of formula (VIII) or (X) are reacted with a compound of formula (XI):
H2NXR9xe2x80x83xe2x80x83(XI)
wherein X and R9 are as defined for formula (I),
to yield a compound of formula (I) which is purified, if necessary, according to a conventional purification technique, is separated, if desired, into isomers according to a conventional separation technique and is converted, if desired, into addition salts with a pharmaceutically acceptable acid or base.
The compound of formula (XI) can be obtained, either starting from the compound of formula (XII):
R9xe2x80x94XHxe2x80x83xe2x80x83(XII),
wherein X and R9 are as defined hereinbefore,
in accordance with the procedure described in Synthesis 1976, pp. 682-683 or in Synthesis 1980, pp.461,
or starting from the compound of formula (XIII)
R9xe2x80x94Clxe2x80x83xe2x80x83(XIII)
wherein R9 is as defined hereinbefore,
in accordance with the procedure described in Tet. Lett. 1997, 38, p. 7233.
In addition to the fact that the compounds of the present invention are new, they exhibit valuable pharmacological properties. They have cytotoxic properties, which render then useful in the treatment of cancers
The invention extends also to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I) together with one or more appropriate, inert, non-toxic excipients. Amongst the pharmaceutical compositions according to the invention there may be mentioned more especially those which are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous) or nasal administration, tablets or dragees, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions etc.
The useful dosage is adaptable in accordance with the nature and severity of the disorder, the administration route, the age and weight of the patient, and any associated treatments.
It varies from 0.5 mg to 2 g per 24 hours taken in one or more administrations.
The Examples which follow illustrate the invention but do not limit it in any way.
The starting materials employed are known products or products prepared in accordance with known procedures.
Preparations A to E result in synthesis intermediates for use in the preparation of the compounds of the invention.
The structures of the compounds described in the Examples were determined according to customary spectrometric techniques (infra-red, NMR, mass spectrometry).
10 mmol of 5-hydroxy-2-nitrobenzaldehyde dissolved in dimethylformamide are added dropwise to 20 mmol of potassium carbonate suspended in a mixture of dimethyl-formamide and isopropyl ether, and then the reaction mixture is heated at reflux for 2 hours. After the mixture has returned to ambient temperature, 10 mmol of 2-chloro-N,N-dimethylethanamine hydrochloride are added dropwise, and then the reaction mixture is heated at reflux again for one night. After returning to ambient temperature, the mixture is filtered and the solvents of the filtrate are evaporated off to yield the expected product in the form of an oil.
The expected product is obtained in accordance with the procedure described in Preparation A, starting from 5-hydroxy-2-nitrobenzaldehyde and 1-(2-chloroethyl)-piperidine hydrochloride.
The expected product is obtained in accordance with the procedure described in Preparation A, starting from 5-hydroxy-2-nitrobenzaldehyde and 1-(2-chloroethyl)-pyrrolidine.
The expected product is obtained in accordance with the procedure described in Preparation A, starting from 5-amino-2-nitrobenzaldehyde and 2-chloro-N,N-dimethyl-ethanamine hydrochloride.
The expected product is obtained in accordance with the procedure described in Preparation A, starting from 5-hydroxy-2-nitrobenzaldehyde and 2-chloro-N,N-diethyl-ethanamine hydrochloride.